EP0349797B1 - Composition pharmaceutique stabilisée contenant de l'acétylcystéine - Google Patents

Composition pharmaceutique stabilisée contenant de l'acétylcystéine Download PDF

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Publication number
EP0349797B1
EP0349797B1 EP89110619A EP89110619A EP0349797B1 EP 0349797 B1 EP0349797 B1 EP 0349797B1 EP 89110619 A EP89110619 A EP 89110619A EP 89110619 A EP89110619 A EP 89110619A EP 0349797 B1 EP0349797 B1 EP 0349797B1
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EP
European Patent Office
Prior art keywords
ascorbic acid
acetylcysteine
ascorbate
acetyl cysteine
parts
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP89110619A
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German (de)
English (en)
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EP0349797A1 (fr
Inventor
Fritz Dr. Stanislaus
Fritz-Heinrich Klemm
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Astellas Deutschland GmbH
Original Assignee
Klinge Pharma GmbH and Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Klinge Pharma GmbH and Co filed Critical Klinge Pharma GmbH and Co
Priority to AT89110619T priority Critical patent/ATE81000T1/de
Publication of EP0349797A1 publication Critical patent/EP0349797A1/fr
Application granted granted Critical
Publication of EP0349797B1 publication Critical patent/EP0349797B1/fr
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/195Carboxylic acids, e.g. valproic acid having an amino group
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones

Definitions

  • the invention relates to a stabilized pharmaceutical preparation, in particular a stabilized drug containing N-acetylcysteine, and the use of ascorbic acid or ascorbate to stabilize the same.
  • N-acetylcysteine has an expectorant effect in various diseases of the lungs and bronchi.
  • Acetylated cysteine is characterized by increased stability compared to the starting substance cysteine in the body. This is due to the fact that the orally ingested active ingredient is not only reversibly bound to protein as a free substance, but also via disulfide bridges or is firmly incorporated into proteins. The unstable disulfide bond between N-acetylcysteine and proteins can therefore be regarded as a protective form.
  • the active ingredient does not enjoy such protection in aqueous solution or dispersion, especially not if, according to the recommendation in the medication package insert, the commercially available granules are dissolved in water, tea or fruit juices for ingestion. Then there is a risk that, especially when dissolved in a warm medium, the active substance will decompose.
  • the extent of the decomposition is particularly strong if the active ingredient after dissolution in e.g. warm water or tea is not taken straight away, but left to stand for some time. For example, It is found that when a medicinal product containing N-acetyl is dissolved in tea heated to approx. 70 ° C under conditions such as those in a thermos flask, thermos flask or on a hotplate, a significant amount of the active ingredient is obtained after approx is decomposed.
  • JP 49/92219 describes the stabilization of aqueous ascorbic acid solutions by adding non-therapeutic amounts of N-acetylcysteine and sulfite.
  • a stabilization of aqueous N-acetylcysteine solutions by ascorbic acid cannot be derived from the above-mentioned prior art, especially taking into account the respective oxidation potentials of ascorbic acid and N-acetylcysteine.
  • Ascorbic acid has a standard oxidation potential of -0.115 volts at pH 5.2 (30 ° C) and of -0.140 volts at pH 4.7 (30 ° C) (Stewart, PJ, Tucker, IG, Aust. J. , Hosp. Pharm., 15 (2), 1985, page 111 ff.). It can be assumed that the oxidation mechanism of N-acetylcysteine is comparable to that of cysteine and thus a standard oxidation potential similar to that of cysteine can be assumed for N-acetylcysteine. Cysteine has a standard oxidation potential of +0.220 volts (25 ° C) (see above publication by P.J. Stewart et al.).
  • the object of the present invention is to provide a stabilized medicament containing N-acetylcysteine.
  • the drug to be stabilized containing N-acetylcysteine is in solid form or as an aqueous solution or dispersion, and is preferably brought into aqueous solution for use on humans. It is preferred to dissolve the N-acetylcysteine-containing drug for ingestion in a warm medium, in which it is
  • the form stabilized according to the invention essentially retains its effectiveness even when left to stand for a longer period of time.
  • the amounts by weight of ascorbic acid or a salt thereof added for stabilization can vary in the range from 5 to 100 parts by weight, preferably from 10 to 50 parts by weight, in each case based on 100 parts by weight of N-acetylcysteine.
  • the amount of ascorbic acid or ascorbate is particularly preferably 25 parts by weight per 100 parts by weight of N-acetylcysteine.
  • the invention also encompasses the use of ascorbic acid or a salt thereof for the stabilization of medicaments containing N-acetyl.
  • N-acetylcysteine achieved according to the invention is surprising insofar as it was not to be expected due to the oxidation potentials of N-acetylcysteine on the one hand and ascorbic acid on the other hand.
  • the stabilizing effect according to the invention is generally evident when N-acetylcysteine is dissolved in an aqueous medium and left to stand for some time. This effect is particularly pronounced when the drug is dissolved in warm tea; in this case, the decomposition of the active ingredient, which is accelerated by the presence of tea ingredients such as flavones, tannins, etc., is largely prevented. The decomposition of N-acetylcysteine is thus significantly reduced due to the stabilizing effect of ascorbic acid. This effect is all the more advantageous because the physiological tolerability and safety of ascorbic acid cannot be disputed, a fact that is not true for all antioxidants.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Claims (8)

1 - Médicament contenant de la N-acétylcystéine stabilisée, caractérisé en ce qu'il comprend une quantité thérapeutiquement active de N-acétylcystéine et, comme seul stabilisant, de l'acide ascorbique ou un ascorbate.
2 - Médicament selon la revendication 1, caractérisé en ce qu'il se présente sous forme solide, de solution ou de dispersion aqueuse.
3 - Médicament selon les revendications 1 ou 2, caractérisé en ce que pour l'administration à l'homme il est amené sous forme de solution aqueuse.
4 - Médicament selon les revendications 1 à 3, caractérisé en ce que l'acide ascorbique ou l'ascorbate sont présents dans un rapport pondéral de 5 à 100 parties pour 100 parties de N-acétylcystéine.
5 - Médicament selon la revendication 4, caractérisé en ce que l'acide ascorbique ou l'ascorbate sont présents dans un rapport pondéral de 10 à 50 parties pour 100 parties de N-acétylcystéine.
6 - Médicament selon la revendication 4, caractérisé en ce que l'acide ascorbique ou l'ascorbate sont présents dans un rapport pondéral de 25 parties pour 100 parties d'acétylcystéine.
7 - Utilisation de l'acide ascorbique ou de l'ascorbate pour la stabilisation de médicaments contenant de la N-acétylcystéine comme seul stabilisant, la N-acétylcystéine étant présente dans une quantité thérapeutiquement active.
8 - Utilisation selon la revendication 7, dans laquelle le médicament est présent sous forme de substance solide, de solution ou de dispersion aqueuse.
EP89110619A 1988-06-30 1989-06-12 Composition pharmaceutique stabilisée contenant de l'acétylcystéine Expired - Lifetime EP0349797B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT89110619T ATE81000T1 (de) 1988-06-30 1989-06-12 Stabilisierte, n-acetylcysteinhaltige arzneimittelzubereitung.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE3822096 1988-06-30
DE3822096A DE3822096A1 (de) 1988-06-30 1988-06-30 Stabilisierte arzneimittelzubereitung

Publications (2)

Publication Number Publication Date
EP0349797A1 EP0349797A1 (fr) 1990-01-10
EP0349797B1 true EP0349797B1 (fr) 1992-09-30

Family

ID=6357629

Family Applications (1)

Application Number Title Priority Date Filing Date
EP89110619A Expired - Lifetime EP0349797B1 (fr) 1988-06-30 1989-06-12 Composition pharmaceutique stabilisée contenant de l'acétylcystéine

Country Status (5)

Country Link
EP (1) EP0349797B1 (fr)
AT (1) ATE81000T1 (fr)
DE (2) DE3822096A1 (fr)
ES (1) ES2043959T3 (fr)
GR (1) GR3005848T3 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GR1007236B (el) * 2009-12-07 2011-04-08 Uni-Pharma Κλεων Τσετης Φαρμακευτικα Εργαστηρια Αβεε Με Δ.Τ. Uni-Pharma Abee, Νεα φαρμακευτικη συνθεση κοκκιων ν - ακετυλοκυστεϊνης και μεθοδος παραγωγης αυτων

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4103360A1 (de) * 1991-02-05 1992-08-06 Koehler Peter Medikament zur linderung und heilung von asthma bronchiale und anderen lungenerkrankungen
DE4327462A1 (de) * 1993-08-16 1995-02-23 Carl Heinrich Dr Weischer Neue N-Acetyl-p-Aminophenol-Derivate zur Bekämpfung von Schmerzzuständen
DE4406261C2 (de) * 1993-08-31 1996-07-04 Deutsches Krebsforsch Verwendung von Thiolverbindungen zur Verminderung der Körperfettmenge
DE4329857C2 (de) * 1993-09-03 1995-08-24 Deutsches Krebsforsch Verbindung zur Stärkung des Immunsystems und von Immunreaktionen
IN2000KO00299A (fr) * 1999-05-28 2005-11-18 Johnson & Johnson Consumer
TR200900881A2 (tr) * 2009-02-05 2010-08-23 Bi̇lgi̇ç Mahmut Tadı ve kokusu maskelenmiş stabil farmasötik bileşimler
US10682324B2 (en) * 2015-01-27 2020-06-16 Florengale, Llc Healing topical composition

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2336176C2 (de) * 1972-07-14 1987-01-22 Richard Albert Silverspring Passwater, Md. Als Nahrungs- und Futter-Zusatzmittel geeignetes Mittel mit Antialterungs-, Tumorverhütungs- und Antitumorwirkung
CH667590A5 (it) * 1986-07-24 1988-10-31 Inpharzam Int Sa Composizione farmaceutica effervescente idrosolubile contenente n-acetil-cisteina. .

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Band 96, Nr. 9, 01 März 1982, Columbus, OH (US); R.R.PFISTER et al., Seite 62, Nr. 62950a. *
INVEST. OPHTALMOL. VIS. SCI., Band 25, Nr. 3, September 1981; Seiten 486-490. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GR1007236B (el) * 2009-12-07 2011-04-08 Uni-Pharma Κλεων Τσετης Φαρμακευτικα Εργαστηρια Αβεε Με Δ.Τ. Uni-Pharma Abee, Νεα φαρμακευτικη συνθεση κοκκιων ν - ακετυλοκυστεϊνης και μεθοδος παραγωγης αυτων

Also Published As

Publication number Publication date
DE58902357D1 (de) 1992-11-05
ES2043959T3 (es) 1994-01-01
ATE81000T1 (de) 1992-10-15
EP0349797A1 (fr) 1990-01-10
GR3005848T3 (fr) 1993-06-07
DE3822096A1 (de) 1990-01-04

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